JP2998592B2 - Method for producing phosphonic acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing N-acylaminomethylphosphonic acid and aminomethylphosphonic acid which are useful as an intermediate for synthesizing N-phosphonomethylglycine or a salt thereof known as a herbicide drug substance.

[0002]

2. Description of the Related Art There have been known several methods for producing N-acylaminomethylphosphonic acids. The production method of the present invention, namely, a method comprising reacting N-methylolamide with phosphorous acid in the presence of a halogenating agent. Are novel methods that have not been known at all, and they give satisfactory results for problems that could not be realized by the prior art, and can be said to be industrially superior methods.

Conventional typical methods have various difficulties as described below and have many practical problems. Liebigs Ann.Ch
em. (9), 861-7 (1988) describe the reaction of 1,3,5-triacetylhexahydro-1,3,5-triazine with phosphorus trichloride or phosphite diester to give N-acetylaminomethylphosphonic acid. And methods for producing the esters thereof. However, these methods use a special solvent such as dimethyl sulfoxide or hexamethylphosphoric triamide, and the starting materials 1,3,
It is difficult to obtain 5-triacetylhexahydro-1,3,5-triazine and there are various difficulties, and N-acylaminomethylphosphonic acid and its diethyl ester are produced by these methods on a commercial scale. It is difficult. Synthetic Communications, 16, (7), 733-739 (198
6) discloses a method for producing dimethyl N-benzoylaminomethylphosphonate by reacting N-methylolbenzamide with a mixture of phosphorus trichloride and trimethyl phosphite. This ester is hydrolyzed by an acid to produce aminomethylphosphonic acid. However, trimethyl phosphite used in these methods is relatively expensive and thus has a great economic disadvantage.

In US Pat. No. 2,328,358 and US Pat. No. 2,304,156, N-methylolamide is reacted with phosphorus trihalide without solvent, and then contacted with excess water to give N-acylaminomethylphosphonate. A method for producing an acid is disclosed. However, these methods generally have various disadvantages such as low yield, long reaction time, and use of expensive amide raw materials. European Patent 37
In 0.992, acetamide and paraformaldehyde were treated in acetic acid, and phosphorus trichloride was added to react.
A method for producing aminomethylphosphonic acid by subjecting the obtained N-acetylaminomethylphosphonic acid to acid or alkali hydrolysis is disclosed.Poland Patent 117780 discloses that N-methylolbenzamide is converted to phosphorus trichloride in acetic acid. A method for producing aminomethylphosphonic acid by reacting and hydrolyzing the obtained N-benzoylaminomethylphosphonic acid is disclosed. Although these methods show relatively good yields, in carrying out this method, an equimolar amount or more of a raw material called phosphorus trichloride, which is somewhat difficult to handle, is used. It is difficult to recover the gas due to the generation of an excess gas of 3 moles, acetyl chloride is by-produced and extra time is required for the separation and recovery, and it is extremely difficult to separate and recover the solvent acetic acid and water. Therefore, it has been difficult to produce acylaminomethylphosphonic acid and aminomethylphosphonic acid by these methods on a commercial scale.

To solve the problem of the separation step, Japanese Patent Application Laid-Open No. 5-112586 discloses a method in which an N-methylolamide compound and phosphorus trihalide are mixed at 60-160 ° C. in an aprotic solvent in the presence of water. And a reaction method for obtaining N-acylaminomethylphosphonic acid by contacting with water after heating to a temperature of 2. This method is an excellent method in that the yield is high, the reaction is easy to control, and the step of separating the target substance from the reaction solution is not complicated. However, since phosphorus trichloride is used as a raw material, the handling of the raw material is difficult. ,
It has problems such as generation of excess hydrochloric acid.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide an N-
In the method for producing acylaminomethylphosphonic acid, use of inexpensive, readily available and easy-to-handle materials, high yield, simple and easy reaction steps, and low amount of hydrogen halide generated It is an object of the present invention to solve the problems of the conventional methods and to develop an industrially superior production method.

[0007]

Means for Solving the Problems The present inventors have completed the present invention as a novel method for producing N-acylaminomethylphosphonic acid which solves the above-mentioned problems. That is, the present invention
N-acylaminomethylphosphonic acid is produced by reacting N-methylolamide and phosphorous acid in the presence of a halogenating agent at a temperature of 30 to 160 ° C. and then contacting with a large amount of water. About the method.

Hereinafter, the method of the present invention will be described in more detail. N-methylolamide, which is a starting material in the present invention, is described in, for example, DE 262,148 or DE 29
1,712, German Patent 158,088, Monatsh., 78,
172-3 (1948), etc., obtained by reacting an amide with formaldehyde in an alkaline or acidic state.
The N-methylolamide obtained here may be used after isolation, but can be used without particular isolation. N-methylolamide used as a starting material can be represented, for example, by the following general formula RC (O) NHCH ₂ OH. Wherein R is H, a lower alkyl group,
N-methylolamide representing an aryl group or a methylolamino group is preferred as a starting material in the present invention.

The lower alkyl group is a branched or linear C ₁ -C ₅ alkyl group, and the aryl group is a phenyl group or a methylolamino group which may have a substituent which is inert to phosphorous acid or a halogenating agent. Groups are preferred. Typical N-methylolamides are, for example, N, N'-dimethylolurea, N-methylolacetamide, N-methylolformamide, N-methylolpropionamide, N-methylol- (t-, i- or n
-) Butylamide, N-methylol- (t-, i- or n-) valeroamide, N-methylolbenzamide, N
-Methylol- (o-, m- or p-) toluamide, N
-Methylol- (o-, m- or p-) methoxybenzamide, N-methylol- (o-, m- or p-) ethoxybenzamide, N-methylol- (o-, m- or p-) chlorobenzamide, N-methylol- (o-,
m- or p-) nitrobenzamide, N-methylol-
(2,3-, 2,4-, 2,5-, 2,6-, 3,4-
Or 3,5) dichlorobenzamide and the like, preferably N, N'-dimethylol urea, N- methylol acetamide and the like, each corresponding N- acyl amino methyl phosphonic acid _{RC (O) NHCH 2 P (} O) (O
H) ₂ is obtained (however, in the case of N, N'-dimethylolurea, R is a phosphonomethylamino group).

The halogenating agent used in the present reaction is a reagent having the ability to convert at least one of the substituents of phosphorous acid into a halogen group. Examples include acyl halide, phosphorous halide, thionyl halide, sulfuryl halide, halocarbonate, halogen and the like.

Specific examples of the acyl halide compound include formyl chloride, acetyl chloride, propionyl chloride, (i- or n-) butyryl chloride, (t-, i- or n-) valeryl chloride, benzoyl chloride, (O-, m- or p-) toluoyl chloride, (o-, m- or p-) methoxybenzoyl chloride, (o-, m- or p-) ethoxybenzoyl chloride, (o-, m- or p -) Chlorobenzoyl chloride, (o-, m- or p-) nitrochlorobenzoyl chloride, formyl bromide, acetyl bromide, propionyl bromide, (i- or n
-) Butyryl bromide, (t-, i- or n-) valeryl bromide, benzoyl bromide, (o-, m-
Or p-) toluoyl bromide, (o-, m- or p
-) Methoxybenzoyl bromide, (o-, m- or p-) ethoxybenzoyl bromide, (o-, m- or p-) chlorobenzoyl bromide, (o-, m- or p-) nitrochlorobenzoyl bromide, formyl Iodide, acetyl iodide, propionyl iodide, (i- or n-) butyryl iodide, (t-,
i- or n-) valeryl iodide, benzoyl iodide, (o-, m- or p-) toluoyl iodide,
(O-, m- or p-) methoxybenzoyl iodide, (o-, m- or p-) ethoxybenzoyl iodide, (o-, m- or p-) chlorobenzoyl iodide, (o-, m -Or p-) nitrochlorobenzoyl iodide. Among them, acyl chlorides are preferable from a practical viewpoint, and formyl chloride, acetyl chloride and benzoyl chloride are particularly preferable.

Specific examples of the phosphorous halide compound include phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, phosphorus oxybromide, phosphorus pentabromide, phosphorus triiodide, phosphorus oxyiodide, and the like.
Phosphorus pentaiodide and the like are preferred. Among them, phosphorous chloride is preferred from a practical viewpoint, and phosphorus trichloride is particularly preferred. Specific examples of the thionyl halide compound include:
Examples thereof include thionyl chloride, thionyl bromide, and thionyl iodide, and among them, thionyl chloride is most preferable from a practical viewpoint.

Specific examples of the sulfuryl halide compound include sulfuryl chloride, sulfuryl bromide, and sulfuryl iodide. Of these, sulfuryl chloride is most preferable from a practical viewpoint. Phosgene is a specific example of the halocarbonate compound. Further, it may be a phosgene dimer or a phosgene trimer. Specific examples of the halogen compound include chlorine, bromine and iodine, and chlorine is preferable from a practical viewpoint.

The initial molar ratio of N-methylolamide and phosphorous acid as the reaction raw materials is 1: 1 which is a chemical equivalent when the halogenating agent used is other than phosphorus trihalide.
(However, when R is a methylolamino group, 1: 2) may be used, but it is not a problem to use one of them in a slight excess. In this case, phosphorous acid is converted to N-methylolamide from a practical viewpoint. It is preferable to use about 1.0 to 1.3 equivalents. When the halogenating agent to be used is other than phosphorus trihalide, the amount of the halogenating agent is 1.0 equivalent to the phosphorous acid (the equivalent shown here is 1 mol of the phosphorous acid and its substituent This is the theoretical number of moles in which one can be converted into a halogen.) It is necessary to carry out the reaction more than that. Conversely, if a large amount of the halogenating agent is used, a large amount of hydrochloric acid gas is generated, the yield is reduced, and by-products are generated.
Process and economic disadvantages are inevitable. Accordingly, the amount of the halogenating agent is preferably 1.0 to 6.0 equivalents, particularly preferably 1.5 to 2.5 equivalents to phosphorous acid.

When the halogenating agent is phosphorus trihalide, the halogenating agent itself changes in the system and acts as a phosphonating reagent. For this reason, the initial charge ratio of phosphorous acid as a reaction raw material is calculated by adding the moles of phosphorus trihalide.
The preferred amount of phosphorus trihalide is from 0.2 to phosphorous acid.
The molar amount is 5.0 times, particularly preferably 0.5 to 2 times. If the molar ratio is 0.2 mol or less or 5.0 mol or more, a satisfactory yield cannot be obtained, which is not preferable. When a halogen compound is used as the halogenating agent, a reagent which can activate the halogen compound, for example, a Lewis acid may be used in combination.

The solvent may be used without solvent or may be used. The reaction can be carried out also as a solvent by subjecting the halogenating agent to the reaction in a slightly larger amount. Examples of the solvent used include a polar solvent and a non-polar solvent. Halogenated hydrocarbons as polar solvents,
Ether, polyether, carboxylic acid, carboxylic acid ester, nitrile, aromatic nitro compound and the like can be mentioned.
Examples of these typical compounds include chlorobenzene, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, dichloroethylene, dichlorobenzene propyl ether, isopropyl ether, butyl ether, pentyl ether, isopentyl ether, 1,2
-Dimethoxyethane, digram, tetrahydrofuran, 1,4-dioxane, anisole, formic acid, acetic acid, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, nitrobenzene, acetonitrile, propio Nitriles and the like, among which, from the practical viewpoints such as solubility of the raw material compounds, ease of separation and recovery after the reaction, economical efficiency, particularly, propyl ether, isopropyl ether, butyl ether,
Preferred examples include pentyl ether, isopentyl ether, 1,2-dimethoxyethane, diagram, 1,4-dioxane, acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like.

Examples of the non-polar solvent include aliphatic hydrocarbons and aromatic hydrocarbons. Examples of these typical compounds include, for example, cyclohexane, hexane, heptane, octane, benzene, toluene, xylene, ethylbenzene, mesitylene, etc., among which the dispersibility of the raw material compounds and the ease of separation and recovery after the reaction From the practical viewpoints such as economy and economy, hexane, benzene, toluene, xylene, ethylbenzene and the like are particularly preferable.

A mixture of N-methylolamide and phosphorous acid or a mixture thereof is dissolved in an aprotic solvent, and when a halogenating agent is added to the mixture, it is added at a low temperature for the purpose of controlling the reaction, particularly at 0 to 60 ° C. Is preferred. Reaction 3
The reaction is carried out under a temperature condition of 0 to 160 ° C., for example, it is preferable to gradually raise the temperature of the reaction mixture from room temperature to a temperature exceeding 80 ° C. after adding a halogenating agent. Depending on the presence or absence of the reactants, the halogenating agent and the solvent, the temperature is preferably from 90 to 110 ° C. in order to obtain the maximum yield of the product.

After the temperature of the reaction product is raised, it is brought into contact with a large amount of water.
The temperature condition in that case is preferably 80 ° C. or less. The reaction product N-acylaminomethylphosphonic acid can be isolated as crystals after distilling off water and the reaction solvent.
In addition, the N-acylaminomethylphosphonic acid of the present invention can produce aminomethylphosphonic acid by hydrolysis by a conventionally known method. In this case, even if a mineral acid such as sulfuric acid or hydrochloric acid is used, sodium hydroxide,
Hydrolysis can be easily performed using an alkali metal hydroxide such as potassium hydroxide. However, a direct product when an alkali metal hydroxide is used is an alkali metal salt, and further conversion to aminomethylphosphonic acid requires further neutralization.
As a reaction raw material, N-acylaminomethylphosphonic acid may be subjected to the reaction after isolation and purification, or may be used directly after purification by distilling off the reaction solvent.

Further, aminomethylphosphonic acid obtained by the above reaction can be obtained by a known method, for example, Japanese Patent Application Laid-Open No. 4-2.
N-phosphonomethylglycine or a salt thereof can be produced by the method described in 79595. N-phosphonomethylglycine can be produced by known methods, for example, U.S. Pat. Nos. 3,799,758 and 3,977,860.
According to the method of EP 369076, salts such as substituted amonium salts and trisubstituted sulfonium salts can be efficiently produced.

[0021]

One of the most important requirements in the process of the present invention is to carry out the reaction in the presence of a halogenating agent in the system. The reaction in the absence of a halogenating agent, i.e., N-methylolamide and phosphorous acid alone did not produce any N-acylaminomethylphosphonic acid, resulting in the recovery of the raw material. Further, simply mixing phosphorus trichloride and N-methylolacetamide in dioxane on a water bath at 20 ° C.
When the temperature was raised to ° C. and the reaction was carried out for 3 hours, and then contacted with a large amount of water, N-acetylaminomethylphosphonic acid was obtained, but the yield was as low as about 40%. According to the process of the present invention, the yield exceeds 80% under similar reaction conditions. Therefore, phosphorous acid is simply trihalogenated in the system,
This is fundamentally different from the method in which phosphorus trihalides are formed, which react with N-methylolamide to form N-acylaminomethylphosphonic acids.

The reason why the reaction proceeds due to the presence of the halogenating agent in the system is not always clear, but first, a certain active phosphorus halide compound comprising phosphorous acid and a halogenating agent, for example, hydroxyphosphonodihalide And dihydroxyphosphonohalide are generated, which react with N-methylolamide to form acylaminomethylphosphonic acid halide, which is presumed to lead to N-acylaminomethylphosphonic acid.

[0023]

EXAMPLES The method of the present invention will be described in more detail with reference to representative examples, which are merely illustrative for explanation. Therefore, it goes without saying that the method of the present invention is not limited to these examples, and is not limited by these examples.

Example 1 17.90 g of acetamide was placed in a 300 ml flask.
(0.30 mol), 95% paraformaldehyde 9.4
8 g (0.30 mol) and 0.20 g (0.002 mol) of a 40% aqueous solution of sodium hydroxide were added. This mixture was heated at 60 ° C. for 1.5 hours to form a solution, and then cooled to N 2
-A methylol acetamide solution was obtained. Into this, 97
29.6 g (0.35 mol) of% phosphorous acid were added. The mixture was cooled in a water ice bath and acetyl chloride 137.3.
7 g (1.75 mol) was gradually added dropwise over about 1 hour with stirring so that the reaction temperature did not exceed 60 ° C.

After completion of the dropwise addition, the solution is heated and stirred for 3 hours.
The reaction temperature was gradually increased to 105 ° C. over time.
After completion of the reaction, the reaction mixture is cooled to room temperature,
Stirred for minutes. After evaporating the solvent under reduced pressure, white crystals were obtained. According to the result of analysis by liquid chromatography, the yield of N-acetylaminomethylphosphonic acid was 7
8% (from acetamide). This product was converted into sodium aminomethylphosphonate by adding 60 g (1.5 mol) of a 25% aqueous sodium hydroxide solution and reacting at 70 ° C. for 3 hours. As a result of analysis by liquid chromatography, the yield was 74%.
(From acetamide). The solution was acidified with concentrated hydrochloric acid and evaporated to dryness. Then, it was poured into 300 ml of concentrated hydrochloric acid to precipitate sodium chloride, which was removed by filtration. The filtrate was evaporated and the residue was recrystallized from water and methanol to give 99% pure aminomethylphosphonic acid.
2.54 g (67% yield (from acetamide)) was obtained.

Example 2 17.90 g of acetamide (0.
30 mol), 95% paraformalmaldehyde 9.4
8 g (0.30 mol), 0.20 g (0.002 mol) of a 40% aqueous solution of sodium hydroxide and 120 ml of 1,4-dioxane were added. The mixture was heated at 60 ° C. for 1.5 hours to form a uniform solution and then cooled to obtain an N-methylolacetamide solution. Into this, 97% phosphorous acid 29.
6 g (0.35 mol) were added. The mixture was cooled in a water-ice bath, and 54.95 g (0.70 mol) of acetyl chloride was stirred for about 1 hour under stirring so that the reaction temperature did not exceed 60 ° C.
It was dropped slowly over time. The solution was heated and the reaction temperature was gradually increased to 100 ° C. over 3 hours with stirring.

After completion of the reaction, the reaction mixture was cooled to room temperature,
and stirred for 30 minutes. After evaporating the solvent under reduced pressure, white crystals were obtained. According to the result of analysis by liquid chromatography, the yield of N-acetylaminomethylphosphonic acid was 85% (from acetamide). 60 g of a 25% aqueous solution of sodium hydroxide (1.
5 mol) and reacted at 70 ° C. for 3 hours to convert into aminomethylphosphonic acid sodium salt. As a result of analysis by liquid chromatography,
The yield was 81% (from acetamide).

Example 3 35.80 g of acetamide was placed in a 100 ml flask.
(0.60 mol), 40% aqueous sodium hydroxide solution 0.1.
40 g (0.004 mol) and 18.96 g (0.60 mol) of 95% paraformaldehyde were charged. The mixture was heated at 60 ° C. for 1.5 hours and then cooled to 5 ° C. for crystallization. The crystals were recrystallized from 30 ml of 1,4-dioxane to obtain 48.19 g (88% yield) of 98% pure N-methylolacetamide.

In a 500 ml flask, the N-
26.73 g (0.3 mol) of methylolacetamide
After weighing out, 120 ml of 1,4-dioxane was added and dissolved. 29.6 g of 97% phosphorous acid (0.35
Mol) was added. The mixture was cooled in a water-ice bath and 54.95 g (0.70 mol) of acetyl chloride was gradually added dropwise over about 1 hour with stirring so that the reaction temperature did not exceed 60 ° C. The solution was heated and the reaction temperature was gradually increased to 100 ° C. over 3 hours with stirring. After the reaction,
After cooling to room temperature, 120 ml of water was added and the mixture was stirred for 30 minutes. After evaporating the solvent under reduced pressure, white crystals were obtained.
According to the result of analysis by liquid chromatography, the yield of N-acetylaminomethylphosphonic acid was 92% (from N-methylolacetamide). In this product,
By adding 60 g (1.5 mol) of a 25% aqueous solution of sodium hydroxide and reacting at 70 ° C. for 3 hours, it was possible to convert to sodium aminomethylphosphonate.
As a result of analysis by liquid chromatography, the yield was 87.
% (From N-methylolacetamide).

Example 4 36.71 g of benzamide instead of acetamide
(0.30 g) was performed in the same manner as in Example 2 except that (0.30 g) was used. As a result of analysis by liquid chromatography, the yield of N-benzoylaminomethylphosphonic acid was 88%, and the yield of aminomethylphosphonic acid was 84% (from benzamide).

Comparative Example 1 17.90 g of acetamide was placed in a 300 ml flask.
(0.30 mol), 95% paraformaldehyde 9.4
8 g (0.30 mol), 0.20 g (0.002 mol) of a 40% aqueous solution of sodium hydroxide and 120 ml of 1,4-dioxane were charged. The mixture is brought to 60 ° C., 1.5
After heating for hours to form a solution, the solution was cooled to obtain an N-methylolacetamide solution. Into this, 97% phosphorous acid 29.6
g (0.35 mol) was added. The solution was heated and the reaction temperature was gradually increased to 100 ° C. over 3 hours with stirring. After completion of the reaction, was cooled to room temperature, was directly stirred for 30 minutes added water 120 ml, N is ³¹ P-NMR analysis
-Acetylaminomethylphosphonic acid was not generated at all, and analysis by liquid chromatography revealed that N-methylolacetamide remained as it was.

Comparative Example 2 17.90 g of acetamide (0.
30 mol), 95% paraformalmaldehyde 9.4
8 g (0.30 mol), 0.20 g (0.002 mol) of a 40% aqueous solution of sodium hydroxide and 120 ml of 1,4-dioxane were added. The mixture was heated at 60 ° C. for 1.5 hours to form a uniform solution and then cooled to obtain an N-methylolacetamide solution. The mixture was cooled in a water-ice bath, and 48.07 g (0.35 mol) of phosphorus trichloride was added at a reaction temperature of 6%.
The solution was gradually added dropwise over about 1 hour with stirring so as not to exceed 0 ° C. The solution was heated and the reaction temperature was gradually increased to 100 ° C. over 3 hours with stirring.

After the completion of the reaction, the reaction mixture was cooled to room temperature,
and stirred for 30 minutes. After evaporating the solvent under reduced pressure, white crystals were obtained. According to the result of analysis by liquid chromatography, the yield of N-acetylaminomethylphosphonic acid was 40% (from acetamide). 60 g of a 25% aqueous solution of sodium hydroxide (1.
5 mol) and reacted at 70 ° C. for 3 hours to convert into aminomethylphosphonic acid sodium salt. As a result of analysis by liquid chromatography,
The yield was 38% (from acetamide).

Example 5 17.90 g of acetamide (0.
30 mol), 95% paraformalmaldehyde 9.4
8 g (0.30 mol), 0.20 g (0.002 mol) of a 40% aqueous solution of sodium hydroxide and 30 ml of 1,4-dioxane were added. The mixture was heated at 60 ° C. for 1.5 hours to form a uniform solution and then cooled to obtain an N-methylolacetamide solution. 8.43 g (0.10 mol) of 97% phosphorous acid, 34.33 phosphorus trichloride in a 500 ml flask
(0.25 mol) and 50 ml of dioxane. The mixture was cooled in a water-ice bath, and the N-methylolacetamide solution was stirred for about 1 hour so that the reaction temperature did not exceed 60 ° C.
It was dropped slowly over time. The solution was heated and the reaction temperature was gradually increased to 100 ° C. over 3 hours with stirring.

After completion of the reaction, the reaction mixture was cooled to room temperature,
and stirred for 30 minutes. After evaporating the solvent under reduced pressure, white crystals were obtained. According to the result of analysis by liquid chromatography, the yield of N-acetylaminomethylphosphonic acid was 78% (from acetamide). 60 g of a 25% aqueous solution of sodium hydroxide (1.
5 mol) and reacted at 70 ° C. for 3 hours to convert into aminomethylphosphonic acid sodium salt. As a result of analysis by liquid chromatography,
The yield was 74% (from acetamide).

Example 6 The same as Example 5 except that the charged amount of 97% phosphorous acid was 10.14 g (0.12 mol) and the charged amount of phosphorus trichloride was 31.59 (0.23 mol). I went to. As a result of analysis by liquid chromatography, the yield of N-acetylaminomethylphosphonic acid was 82%, and the yield of aminomethylphosphonic acid sodium salt was 78%. (From acetamide)

Example 7 36.71 g of benzamide instead of acetamide
(0.30 mol) was used in the same manner as in Example 4. As a result of analysis by liquid chromatography, the yield of N-benzoylaminomethylphosphonic acid was 85%, and the yield of aminomethylphosphonic acid sodium salt was 81% (from benzamide).

Example 8 83.28 thionyl chloride in place of acetyl chloride
(0.70 mol) was carried out in the same manner as in Example 2 except that it was used. As a result of analysis by liquid chromatography, the yield of N-acetylaminomethylphosphonic acid was 71%, and the yield of sodium aminomethylphosphonic acid sodium salt was 67% (from acetamide).

Example 9 A 500 ml flask was charged with 1 N, N'-dimethylolurea.
8.02 g (0.15 mol) was added, and 120 ml of 1,4-dioxane was added and dissolved. Into this, 29.6 g (0.35 mol) of 97% phosphorous acid was added. The mixture was cooled in a water-ice bath to give 54.95 g of acetyl chloride.
(0.70 mol) was gradually added dropwise over about 1 hour with stirring so that the reaction temperature did not exceed 60 ° C. The solution was heated and the reaction temperature was gradually increased to 100 ° C. over 3 hours with stirring. After the completion of the reaction, the resultant is cooled to room temperature, and water 120
Then, the mixture was stirred for 30 minutes. After evaporating the solvent under reduced pressure, white crystals were obtained. According to the result of analysis by liquid chromatography, the yield of N, N'-bisphosphonomethylurea was 90% (from N, N'-dimethylol urea).
Met. After dissolving this product in 300 g of water, 3
30.38 g (0.3 mol) of 6% hydrochloric acid was added, and 90 ° C.
By reacting for 5 hours, it could be converted to aminomethylphosphonic acid. As a result of analysis by liquid chromatography, the yield was 83% (from N, N'-dimethylolurea). The solution was evaporated to dryness, and the residue was recrystallized from water and methanol to obtain 24.90 g of aminomethylphosphonic acid having a purity of 99% (yield 74% (from N, N'-dimethylolurea)). .

Example 10 In a 500 ml flask, 8.43 g (0.1%) of 97% phosphorous acid was added.
0 mol), 34.33 g (0.25 mol) of phosphorus trichloride and 50 ml of dioxane. The mixture was cooled in a water-ice bath and stirred, so that the reaction temperature did not exceed 60 ° C., and 18.02 g (0.15 g) of N, N -′- dimethylolurea previously dissolved in 50 ml of 1,4-dioxane. Mol) was slowly added dropwise over about 1 hour. The solution was heated and the reaction temperature was gradually increased to 100 ° C. over 3 hours with stirring. After the completion of the reaction, the mixture was cooled to room temperature,
and stirred for 30 minutes. After evaporating the solvent under reduced pressure, white crystals were obtained. According to the result of analysis by liquid chromatography, the yield of N, N′-bisphosphonomethylurea was 85% (from N, N′-dimethylol urea). After dissolving this product in 300 g of water, 36
30.38 g (0.3 mol) of hydrochloric acid at 90.degree.
It was possible to convert to aminomethylphosphonic acid by reacting for hours. As a result of analysis by liquid chromatography, the yield was 72% (from N, N'-dimethylolurea).

Example 11 A 500 ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 22.54 g (0.2 mol) of aminomethylphosphonic acid obtained in Example 1
With 100 g of water and 48% aqueous sodium hydroxide solution.
The mixture was dissolved in 40 g (0.4 mol) of the mixed solution and stirred.
The reactor was cooled in water ice, and 28.60 g of a 40% glycolonitrile solution (0.2 mol) was added dropwise over 30 minutes while keeping the reaction solution at 5 ° C or lower. After completion of the dropwise addition, the mixture was returned to room temperature at 5 ° C or lower for 30 minutes and stirred for 1 hour. Then, 16.
80 g of a 48% aqueous sodium hydroxide solution (0.2 mol)
Was added and heated to reflux for 2 hours. The solution after the completion of the reaction was analyzed by liquid chromatography and found to contain 0.19 mol of N-phosphonomethylglycine. The reaction yield was 9 from the starting material aminomethylphosphonic acid and glycolonitrile.
4%, and 63% from acetamide.

After the reaction solution was neutralized to pH 2 with concentrated hydrochloric acid, it was left overnight to crystallize N-phosphonomethylglycine. Thereafter, the crystallized N-phosphonomethylglycine was filtered off. The weight after washing with water and drying was 26.80 g, and the purity determined by liquid chromatography was 98%. The yield from the raw material aminomethylphosphonic acid and glycolonitrile is 78%, and the yield from acetamide is 52%.
Met. The obtained N- was placed in a 100 ml eggplant-shaped flask.
26.80 g of crystals of phosphonomethylglycine (0.16
Mol) and isopropylamine 9.5 dissolved in 2 g of water.
g (0.16 mol) was added and stirred to dissolve. The resulting solution is heated to 100 ° C. under reduced pressure, concentrated and dried,
A crystalline solid was obtained. As a result of ¹ H-NMR and liquid chromatography analysis, this crystalline solid was found to be pure N-phosphonomethylglycine monoisopropylamine salt.

Example 12 First, crystals of N-phosphonomethylglycine were synthesized in the same manner as in Example 11. Water 32 in a 500 ml eggplant-shaped flask
0 g of trimethylsulfonium hydroxide 1
7.63 g (0.16 mol) and 26.80 g (0.16 mol) of synthesized N-phosphonomethylglycine were added. The mixture was stirred in a water ice bath for about 40 minutes, resulting in a clear, homogeneous solution. This solution was heated to 50 ° C. under reduced pressure, concentrated, and dried to obtain a crystalline solid. As a result of ¹ H-NMR and liquid chromatography analysis, this crystalline solid was found to be pure N-phosphonomethylglycine monotrimethylsulfonium salt.

Example 13 The same procedure as in Example 11 was carried out except that the aminomethylphosphonic acid synthesized in Example 9 was used. The reaction yield of N-phosphonomethylglycine in the obtained N-phosphonomethylglycine solution was 95% from the raw material aminomethylphosphonic acid and glycolonitrile, and 70% from N, N, -dimethylolurea. The purity of the isolated crystalline solid N-phosphonomethylglycine is 98%, and the yield from the raw material aminomethylphosphonic acid and glycolonitrile is 7%.
8%, 58% from N, N'-dimethylolurea. The crystalline solid obtained after concentration and drying was ¹ H-N
Analysis by MR and liquid chromatography revealed that the product was pure monoisopropylamine salt of N-phosphonomethylglycine.

Example 14 The same procedure as in Example 12 was carried out except that the aminomethylphosphonic acid synthesized in Example 9 was used. As a result of ¹ H-NMR and liquid chromatography analysis, the crystalline solid obtained after concentration and drying was found to be pure N-phosphonomethylglycine monotrimethylsulfonium salt.

[0046]

According to the method of the present invention, N-methylolamide, phosphorous acid, a halogenating agent, which can be easily synthesized from amide (including urea) and formaldehyde as raw materials, and a very easily available and inexpensive reagent are used. It can be selected and used as appropriate,
Excellent industrial solution that solves the problems of the conventional technology, such as high yield, use of phosphorous acid that is easy to handle as a phosphonating agent, and reduction of the amount of generated hydrogen halide compared with the conventional method. Manufacturing method. The aminomethylphosphonic acid produced by the method of the present invention can be used as a herbicide drug substance by combining known methods.
-It is possible to efficiently produce phosphonomethylglycine or salts thereof.

Continuation of front page (58) Field surveyed (Int.Cl. ⁷ , DB name) C07F 9/38

Claims (6)

(57) [Claims] 1. N-methylolamide and phosphorous acid are reacted in the presence of a halogenating agent at a temperature of 30 to 160 ° C., and then contacted with a large amount of water.
-A process for producing acylaminomethylphosphonic acids. 2. The method for producing N-acylaminomethylphosphonic acid according to claim 1, wherein the halogenating agent is at least one selected from acyl halide, phosphorous halide, thionyl halide, sulfuryl halide, halocarbonate, and halogen. Law. 3. The method for producing N-acylaminomethylphosphonic acid according to claim 1, wherein the halogenating agent is acyl chloride or phosphorous chloride. 4. A reaction between N-methylolamide and phosphorous acid in the presence of a halogenating agent at a temperature of 30 to 160 ° C., followed by contact with a large amount of water to obtain N-acylaminomethylphosphonic acid. preparation of aminomethyl phosphonate phosphate, characterized in that the hydrolysis is carried out without then obtained N- acyl aminomethylphosphonic acid tied up isolate or single a. 5. The method for producing aminomethylphosphonic acid according to claim 4, wherein the N-methylolamide is N, N′-dimethylolurea. 6. The method according to claim 4, wherein
Methylphosphonic acid and then the resulting aminomethyl
Sulfonic acid to N-phosphonomethylglycine or its salt
A process for producing N-phosphonomethylglycine or a salt thereof.